HOMING IN ON HORNERIN: BREAKING DOWN THE BARRIER TO UNDERSTAND ITS CRUCIAL ROLE IN ATOPIC DERMATITIS

By Warren R. Heymann, MD, FAAD
Oct. 16, 2024
Vol. 6, No. 42

Atopic dermatitis (AD) is characterized by skin barrier dysfunction, inflammation, and chronic pruritus. The etiology of AD, however, is complicated and incompletely understood, with genetic, environmental (soaps, surfactants, stress), and immunological factors causing skin barrier abnormalities and immune dysregulation. This commentary will focus on some new concepts related to the skin barrier. 

The epidermal barrier has three primary functions: 1) limiting passive water loss, 2) restricting environmental chemical absorption, and 3) preventing microbial infection. The epidermis achieves these goals via keratinization to form corneocytes whose main components include loricrin, involucrin, and filaggrin (filament aggregating protein, FLG). Each corneocyte is enveloped by specialized intercellular lipids (ceramides, cholesterol, and free fatty acids [FFA], present in an approximately equimolar ratio) — this combination of "bricks" (corneocytes) and "mortar" (lipids) remains a good model of the skin barrier. (1,2)

According to Elias and Wakefield, "Lamellar bodies, organelles unique to the epidermis, secrete precursors of these lipids, along with lipid hydrolases that generate the three lipids required to form these lamellar membranes. Notably, a lamellar body secretory system also regulates desquamation by co-delivering kallikreins and other proteases that digest corneodesmosomes, leading eventually to corneocyte desquamation. Two antimicrobial peptides, human β-defensin 2 and the cathelicidin peptide LL-37, also known LB cargo, are delivered in parallel with the lipid and enzyme contents noted above. Thus, these two skin "barriers" — the antimicrobial and permeability — share several characteristics, including: i) blockade of pathogen invasion; ii) competition for niche occupancy with normal flora; iii) production of both peptide and peptide ingredients that block pathogen colonization; and iv)most importantly, the acidic surface of the skin, which is hostile to the growth of pathogens such as Staphylococcus (S.) aureus and other Streptococci. Indeed, these two critical defensive functions overlap to an extent that they can be considered as integrated and interrelated." (2)

Regarding immune dysregulation, two different hypotheses have been proposed, from inside to outside and from outside to inside. The former suggests that immunological aberrations are believed to be the primary event, followed by stimulation with allergens, leading to the weakening of the epidermal barrier. The latter hypothesis is that an impaired skin barrier is the initial step in AD pathogenesis and is required for immune dysregulation to occur. (3)

Image from JAAD Int. 2021 Jun 1;4:28-31.

According to Savva et al, "The dysregulated T cell-mediated immune response, including different patterns of cytokine release, has a strong and robust role in the pathogenesis of AD. The disrupted skin barrier enhances exposure to environmental allergens, which can either activate skin antigen-presenting cells, such as the inflammatory dendritic epidermal cells (IDECs), resulting in the subsequent 'allergic response,' or induce the chemokine milieu from keratinocytes, such as the thymic stromal lymphopoietin (TSLP), and interleukins (IL)-23, IL-25, and IL-33, reinforcing the T2 response and the induction of IL-4 and IL-13 [the two main T2-cytokines associated with AD pathogenesis], IL-31 cytokines though type 2 human innate lymphoid cells. This, in turn, promotes the class switch of B cells to plasmacytes toward specific IgE induction. Nevertheless, in chronic AD cases, a TH1 and TH17 dominance is noted, mediated by interferon-gamma (IFN-γ)/tumor necrosis factor-alpha (TNF-α) and IL-17, respectively, while TH22 responses driven by IL-22, are also present." (4)

Genetic alterations are primarily due to loss-of-function mutations of FLG, an epidermal protein that is broken down into natural moisturization factor. FLG mutations are present in up to 30% of AD patients and may also predispose patients to ichthyosis vulgaris, allergic rhinitis, and keratosis pilaris. (5) FLG is a member of the S100 fused-type protein family that also includes cornulin, filaggrin-2 (FLG2), hornerin (HRNR), repetin (RPTN), trichohyalin (TCHH), and trichohyalin-like 1 (TCHHL1). (6) Although FLG mutations account for most AD patients of northern European ancestry, recent studies show that AD is also associated with mutations in the genes encoding two other S-100 proteins — HRNR and FLG2. Rather than FLG, FLG2 mutations instead are associated with AD in African Americans. Although HRNR and FLG2 are components of the corneocyte envelope, their function(s) in normal epidermis remain poorly understood. (2)

In 2001 HRNR was identified in a mouse model and was believed to be similar to profilaggrin, having a role in cornification. (7) Human HRNR was subsequently found in psoriatic skin. (8) Makino et al. sought to clarify the role of HRNR in AD. "HRNR was detected in chronic AD lesions (n = 4), whereas no HRNR signals were observed in acute AD lesions (n = 3). HRNR was detected in the cytokeratin 6-expressing epidermis, and Ki67-positive keratinocytes were more abundant in the HRNR-positive epidermis. These findings suggest that HRNR may be associated with epidermal hyperproliferation in AD lesions." (9) I have often wondered how AD transitions to a chronic, lichenified dermatosis; perhaps HRNR is involved in this phenomenon.

In conclusion, although newer therapies such as monoclonal antibodies (dupilumab, tralokinumab) and JAK inhibitors (upadacitnib, abrocitinib) are in the limelight, replenishing the skin barrier should always be a cornerstone of treating AD.

Point to Remember: Maintaining the skin barrier is crucial in managing patients with atopic dermatitis. The pathomechanism(s) of barrier impairment is complex and integrally associated with immune dysregulation. Research on newly discovered proteins in the stratum corneum, such as hornerin, may lead to novel therapeutic interventions. 

Our expert's viewpoint

Jack L. Arbiser, MD, PhD, FAAD
Thomas J. Lawley Professor of Dermatology, Emeritus
Emory University School of Medicine

Atopic dermatitis is an exceedingly common inflammatory dermatitis, often characterized by itch, bacterial colonization, and, in its chronic states, skin thickening. Contributing factors to the development of AD include mutations in proteins of the stratum corneum, such as filaggrin 1 and 2. Altered expression of these proteins transmits signals to the nucleus to transcribe cytokines such as IL4 and IL13, eventually leading to hyperproliferative stimuli such as IL-22, which results in lichenification and VEGF/Angiopoetin like 4 (Angptl4), resulting in erythema. Th2 inflammation is suppressed by a ceramide-IL-12 pathway, and an intact barrier is maintained by a tonic level of ceramides.

Makino describes an additional protein of the stratum corneum, called hornerin, which may play a role in the development of atopic dermatitis. Low levels of hornerin are seen in acute AD, while the protein is expressed in high levels in lichenified and chronic lesions. It may be that polymorphisms of hornerin, leading to low expression, may predispose to AD. The chronic lichenifcation state of hornerin may represent a futile effect to repair the barrier function, resulting in a thickened yet impaired epidermis. Understanding the regulation of hornerin expression may result in improved therapies for AD.

1. Yang G, Seok JK, Kang HC, Cho YY, Lee HS, Lee JY. Skin Barrier Abnormalities and Immune Dysfunction in Atopic Dermatitis. Int J Mol Sci. 2020 Apr 20;21(8):2867. doi: 10.3390/ijms21082867. PMID: 32326002; PMCID: PMC7215310.

2. Elias PM, Wakefield JS. Could cellular and signaling abnormalities converge to provoke atopic dermatitis? J Dtsch Dermatol Ges. 2020 Nov;18(11):1215-1223. doi: 10.1111/ddg.14232. Epub 2020 Oct 13. PMID: 33048449.

3. Sroka-Tomaszewska J, Trzeciak M. Molecular Mechanisms of Atopic Dermatitis Pathogenesis. Int J Mol Sci. 2021 Apr 16;22(8):4130. doi: 10.3390/ijms22084130. PMID: 33923629; PMCID: PMC8074061.

4. Savva M, Papadopoulos NG, Gregoriou S, Katsarou S, Papapostolou N, Makris M, Xepapadaki P. Recent Advancements in the Atopic Dermatitis Mechanism. Front Biosci (Landmark Ed). 2024 Feb 22;29(2):84. doi: 10.31083/j.fbl2902084. PMID: 38420827.

5. Kolb L, Ferrer-Bruker SJ. Atopic Dermatitis. 2023 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 28846349.

6. Makino T, Mizawa M, Takemoto K, Yamamoto S, Shimizu T. Altered expression of S100 fused-type proteins in an atopic dermatitis skin model. Exp Dermatol. 2023 Dec;32(12):2160-2165. doi: 10.1111/exd.14797. Epub 2023 Mar 30. PMID: 36995036.

7. Makino T, Takaishi M, Morohashi M, Huh NH. Hornerin, a novel profilaggrin-like protein and differentiation-specific marker isolated from mouse skin. J Biol Chem. 2001 Dec 14;276(50):47445-52. doi: 10.1074/jbc.M107512200. Epub 2001 Sep 25. PMID: 11572870.

8. Takaishi M, Makino T, Morohashi M, Huh NH. Identification of human hornerin and its expression in regenerating and psoriatic skin. J Biol Chem. 2005 Feb 11;280(6):4696-703. doi: 10.1074/jbc.M409026200. Epub 2004 Oct 26. PMID: 15507446.

9. Makino T, Mizawa M, Takemoto K, Shimizu T. Expression of hornerin in skin lesions of atopic dermatitis and skin diseases. Clin Exp Dermatol. 2024 Feb 14;49(3):255-258. doi: 10.1093/ced/llad297. PMID: 38123340.

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